Selective β2-adrenoreceptor signaling regulates osteoclastogenesis via modulating RANKL production and neuropeptides expression in osteocytic MLO-Y4 cells

The β2-adrenergic receptor (β2-AR) signaling on bone cells is the major contributor in the effect of the sympathetic nervous system on bone turnover. However, it remains unclear whether receptor activator of nuclear factor κ-Β ligand (RANKL) modulation and neuropeptides expression in osteocytes are responsible for the mechanism. This study used β2-AR stimulation to investigate cell cycle and proliferation, the gene and protein expression of RANKL, and osteoprotegerin (OPG), as well as neuropeptides regulation in osteocytic MLO-Y4 cells. Clenbuterol (CLE; a β2-AR agonist) slightly promoted the growth of MLO-Y4 cells in a concentration-dependent effect but had no effect on the proliferation index. And the concentration of 10⁻⁸ M showed a significant increase in the S-phase fraction on day 3 in comparison with the control. Additionally, CLE-promoted osteoclast formation and bone resorption in osteocytic MLO-Y4 cell-RAW264.7 cell cocultures. RANKL expression level and the ratio of RANKL to OPG in MLO-Y4 cells were enhanced in CLE treatment but were rescued by blocking β2-AR signaling. However, neuropeptide Y and α-calcitonin gene-related peptide, two neurogenic markers, were inhibited in CLE treatment of MLO-Y4 cells, which was reversed by a β2-AR blocker. The results indicate that osteocytic β2-AR plays an important role in the regulation of RANKL/OPG and neuropeptides expression, and β2-AR signaling in osteocytes can be used as a new valuable target for osteoclast-related pathologic disease.     

Knockdown of RPL34 inhibits the proliferation and migration of glioma cells through the inactivation of JAK/STAT3 signaling pathway

Ribosomal protein L34 (RPL34), belonging to the L34E family of ribosomal proteins, was reported to be dysregulated in several types of cancers and plays important roles in tumor progression. However, the expression and roles of RPL34 in human glioma remain largely unknown. Thus, the objective of this study was to investigate the expression and role of RPL34 in glioma. We report here that RPL34 is highly expressed in human glioma tissues and cell lines. Knockdown of RPL34 markedly inhibited the proliferation, migration, and invasion, as well as prevented the epithelial-mesenchymal transition phenotype in glioma cells. Further, mechanistic analysis showed that knockdown of RPL34 significantly downregulated the levels of p-JAK and p-STAT3 in glioma cells. Taken together, our findings indicated that knockdown of RPL34 inhibits the proliferation and migration of glioma cells through the inactivation of JAK/STAT3 signaling pathway. Thus, RPL34 may serve as a potential therapeutic target for the treatment of glioma.     

Hsa-miRNA-29a protects against high glucose-induced damage in human umbilical vein endothelial cells

Sustained exposure to high glucose (HG) results in dysfunction of vascular endothelial cells. Hence, diabetic patients often suffer from secondary vascular damages, such as vascular sclerosis and thrombogenesis, which may eventually cause cardiovascular problems. Thus, elucidating how HG results in vascular endothelial cell damage and finding an approach for prevention are important to prevent and treat vascular damages in diabetic patients. In the current study, we first showed that 72-hour exposure to HG-decreased hsa-miRNA-29a and increased the expression of Bcl-2 associated X protein (Bax), which subsequently inhibited Bcl-2 and promoted the expression of apoptotic protease activating factor-1 and activation of caspase-3, thus directly triggering the mitochondrial apoptotic pathway in human umbilical vein endothelial cells (HUVECs). Study of the underlying mechanism showed that hsa-miRNA-29a/Bax plays an essential role in the decreased proliferation and increased apoptosis of HUVECs induced by HG, and overexpression of hsa-miRNA-29a effectively inhibits HG-induced apoptosis and restores the proliferation and tube formation of HUVECs exposed to HG by inhibiting its target gene Bax. In short, our study demonstrates that hsa-miRNA-29a is a promising target for the prevention and treatment of vascular injury in diabetic patients.     

ATG7-enhanced impaired autophagy exacerbates acute pancreatitis by promoting regulated necrosis via the miR-30b-5p/CAMKII pathway

The present study was performed to explore whether and how impaired autophagy could modulate calcium/calmodulin-dependent protein kinase II (CAMKII)-regulated necrosis in the pathogenesis of acute pancreatitis (AP). Wistar rats and AR42J cells were used for AP modeling. When indicated, genetic regulation of CAMKII or ATG7 was performed prior to AP induction. AP-related necrotic injury was positively regulated by the incubation level of CAMKII. ATG7 positively modulated the level of CAMKII and necrosis following AP induction, indicating that there might be a connection between impaired autophagy and CAMKII-regulated necrosis in the pathogenesis of AP. microRNA (miR)-30b-5p was predicted and then verified as the upstream regulator of CAMKII mRNA in our setting of AP. Given that the level of miR-30b-5p was negatively correlated with the incubation levels of ATG7 after AP induction, a rescue experiment was performed and indicated that the miR-30b-5p mimic compromised ATG7 overexpression-induced upregulation of CAMKII-regulated necrosis after AP induction. In conclusion, our results indicate that ATG7-enhanced impaired autophagy exacerbates AP by promoting regulated necrosis via the miR-30b-5p/CAMKII pathway.Subject terms: Cytokines, Acute inflammation     

Characterization of small RNAs in early zebrafish PGCs

Small RNAs, including miRNAs, siRNAs, and PIWI-interacting RNAs (piRNAs), are small noncoding RNAs that are 21-30 nucleotides in length and play important roles...